Neonatal hypofunction of NMDARs during early postnatal development impairs the induction of long-term potentiation in the LPP – DG synapse.
Granule cells undergo LTP through multiple stimulation patterns that mimic PP activity impinging on the DG. These stimulation protocols are physiologically and behaviorally relevant (Lopez-Rojas et al., 2016); among them, theta-burst stimulation (TBS) has been successfully used to induce stable LTP at the MPP and LPP synapses (Lopez-Rojas et al., 2016; Vyleta and Snyder, 2021). Therefore, we applied TBS to the LPP to test the effects of neonatal MK-801 on LTP induction. A stable baseline of LPP fEPSP slope was recorded for 20 min prior to TBS [3 episodes repeated at 10 s; each episode included 5 pulses delivered at 100 Hz and repeated 10 times at 5 Hz (Larson and Munkácsy, 2015)]. Recording continued for 90 min and was followed by perfusion of L-AP4 (20 µM). In the control condition, TBS triggered a marked post-tetanic potentiation (LPP PTP), followed by long-lasting LPP fEPSP slope potentiation (fEPSP at PTP: 213.4 ± 23.13% of baseline; fEPSP 90 min post-TBS: 144.6 ±13.28% of baseline; fEPSP in presence of L-AP4: 23.18 ± 3.82% of baseline; n = 7 slices / 6 animals, traces and black bars in Figure 6a-b). On the other hand, on the MK-801-treated slices, TBS caused a strong PTP but did not induce a sustained increase in the slope of the fEPSP, as illustrated in the green traces and green symbols in Figure 6a-b (fEPSP at PTP: 239.9 ± 18.28% of baseline; fEPSP 90 min post-TBS: 105.5 ± 10.9% of baseline, Mann-Whitney test, P< 0.05 vs. control; fEPSP in presence of L-AP4: 28.01 ± 4.33% of baseline; n = 7 slices / 7 animals). Interestingly, by adjusting a best-fit single exponential decay function, we found that decay of PTP (tau, 𝜏) is faster in MK-801-treated slices than control slices, suggesting short-term plasticity dysregulation (𝜏 in control: 114 ± 23.38 s; 𝜏 in MK-801: 47.03 ± 5.88 s, Mann-Whitney test, P< 0.05: inset in Figure 6b).
The bar graphs in Figure 6c summarize the mean PTP, potentiation, and sensitivity to L-AP4, while the symbols represent the individual experiments for the control condition and MK-801-treated slices. The heatmaps in Figure 6d contrast the magnitude of the potentiation obtained in each slice, and the cumulative probability graph in Figure 6e shows the overall potentiation for control slices (black symbols) vs. MK-801-treated slices (green symbols). Together, these experiments show that the potentiation of the LPP fEPSP is sensitive to the transient hypofunction of NMDARs during early postnatal development.